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dc.contributor.authorMCMANUS, ROSSen
dc.contributor.authorTURNER, GRAHAMen
dc.contributor.authorRYAN, ANTHONYen
dc.date.accessioned2011-03-16T11:57:35Z
dc.date.available2011-03-16T11:57:35Z
dc.date.issued2011en
dc.date.submitted2011en
dc.identifier.citationZhernakova A, Stahl EA, Trynka G, Raychaudhuri S, Festen EA, Franke L, Westra HJ, Fehrmann RS, Kurreeman FA, Thomson B, Gupta N, Romanos J, McManus R, Ryan AW, Turner G, Brouwer E, Posthumus MD, Remmers EF, Tucci F, Toes R, Grandone E, Mazzilli MC, Rybak A, Cukrowska B, Coenen MJ, Radstake TR, van Riel PL, Li Y, de Bakker PI, Gregersen PK, Worthington J, Siminovitch KA, Klareskog L, Huizinga TW, Wijmenga C, Plenge RM, Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci., PLoS genetics, 7, 2, 2011, e1002004en
dc.identifier.issn1553-7390en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/53321
dc.descriptionPUBLISHEDen
dc.description.abstractEpidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5?10(-8) in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P(combined)?=?1.2?10(-12)), rs864537 near CD247 (P(combined)?=?2.2?10(-11)), rs2298428 near UBE2L3 (P(combined)?=?2.5?10(-10)), and rs11203203 near UBASH3A (P(combined)?=?1.1?10(-8)). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5?10(-8) (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.en
dc.description.sponsorshipRMP was supported by grants from the NIH (R01-AR057108, R01-AR056768, U01-GM092691) and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. SR is supported by an NIH Career Development Award (1K08AR055688-01A1). FK is supported by a Marie Curie International Outgoing Fellowship for Career Development from the European Community's FP7 (Grant Agreement number PIOF-GA-2009-237280). The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The work presented is made possible by grants from the Coeliac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative, and partially funded by the Dutch Government (BSIK03009 to CW) and by the Netherlands Organisation for Scientific Research (NWO, VICI grant 918.66.620 to CW). LF received a Horizon Breakthrough grant from the Netherlands Genomics Initiative (93519031) and a VENI grant from NWO (ZonMW grant 916.10.135). AZ received a Rubicon grant from NWO (825.10.002). GT received a Ter Meulen Fund grant from the Royal Netherlands Academy of Arts and Sciences (KNAW). RMcM is supported by a Science Foundation Ireland Grant 09/IN.1/B2640. KAS is supported by a Canada Research Chair, Sherman Family Chair in Genomic Medicine, CIHR grants MOP79321 and IIN84042, and ORF grant RE01061. This work is partly supported by Coordination Theme 1 (Health) of the European Community's FP7, Grant Agreement number HEALTH-F2-2008-223404 (MASTERSWITCH project); by the EU FP6 supported AutoCure; and by the intramural program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases.en
dc.format.extente1002004en
dc.language.isoenen
dc.relation.ispartofseriesPLoS geneticsen
dc.relation.ispartofseries7en
dc.relation.ispartofseries2en
dc.rightsYen
dc.subjectGeneticsen
dc.subjectceliac disease (CD)en
dc.subjectrheumatoid arthritis (RA)en
dc.titleMeta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci.en
dc.typeJournal Articleen
dc.contributor.sponsorNational Institutes of Health (NIH)en
dc.contributor.sponsorNational Institutes of Health (NIH)en
dc.contributor.sponsorNational Institutes of Health (NIH)en
dc.contributor.sponsorEuropean Commissionen
dc.contributor.sponsorEuropean Commissionen
dc.contributor.sponsorNational Institutes of Health (NIH)en
dc.contributor.sponsorScience Foundation Ireland (SFI)en
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/rmcmanusen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/aryan12en
dc.identifier.rssinternalid71780en
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pgen.1002004en
dc.relation.ecprojectidinfo:eu-repo/grantAgreement/EC/FP7/HEALTH-F2-2008-223404
dc.relation.ecprojectidinfo:eu-repo/grantAgreement/EC/FP7/1K08AR055688-01A1
dc.contributor.sponsorGrantNumberU01-GM092691en
dc.contributor.sponsorGrantNumberR01-AR057108en
dc.contributor.sponsorGrantNumberR01-AR056768en
dc.contributor.sponsorGrantNumberPIOF-GA-2009-237280en
dc.contributor.sponsorGrantNumberHEALTH-F2-2008-223404en
dc.contributor.sponsorGrantNumber1K08AR055688-01A1en
dc.contributor.sponsorGrantNumber09/IN.1/B2640en
dc.subject.TCDThemeGenes & Societyen
dc.subject.TCDThemeImmunology, Inflammation & Infectionen
dc.identifier.rssurihttp://dx.doi.org/10.1371/journal.pgen.1002004en


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